Current evidence indicates that morphine and related narcotic agents possess the ability to alter storage, release, and/or receptor actions of endogenous neurohumoral substances, especially the monoamines, in the intestine. These actions of the narcotics account for many of their complicated intestinal actions and result in failure of propulsion. Experiments to date demonstrate that the intestinal spasm induced by narcotics is accompanied by release of 5- hydroxytryptamine (5-HT) from local storage sites. Preliminary experiments indicate that release of 5-HT plays an essential role in the development of the spasmogenic effect of the narcotics. The purposes of this investigation are (1) to identify those components of narcotic action which result in constipating effects, (2) to establish the role of 5-HT and probably other endogenous substances in the development of gastrointestinal responses to the narcotic analgesics, (3) to examine the functional activities of intrinsic nervous elements in gastrointestinal responses to the narcotics, and (4) to determine what pharmacological means can best be employed to selectively enhance or prevent the gastrointestinal responses to the narcotics. These studies will be conducted primarily in isolated sections of dog intestine perfused by the arterial supply. Similar isolated perfused intestine from cats will be tested and intestinal responses will be compared to those obtained in intact animals. These studies will help define the mechanisms of narcotic actions on the intestine, will reveal the roles of several biogenic substances as modulators of physiological activities, and will provide the basis for better and more rational use of the potent analgesic drugs.